Protein Phosphatase 1α and Cofilin Regulate Nuclear Translocation of NF-κB and Promote Expression of the Anti-Inflammatory Cytokine Interleukin-10 by T Cells

Mol Cell Biol. 2018 Oct 29;38(22):e00041-18. doi: 10.1128/MCB.00041-18. Print 2018 Nov 15.

Abstract

While several protein serine/threonine kinases control cytokine production by T cells, the roles of serine/threonine phosphatases are largely unexplored. Here, we analyzed the involvement of protein phosphatase 1α (PP1α) in cytokine synthesis following costimulation of primary human T cells. Small interfering RNA (siRNA)-mediated knockdown of PP1α (PP1KD) or expression of a dominant negative PP1α (D95N-PP1) drastically diminished interleukin-10 (IL-10) production. Focusing on a key transcriptional activator of human IL-10, we demonstrate that nuclear translocation of NF-κB was significantly inhibited in PP1KD or D95N-PP1 cells. Interestingly, knockdown of cofilin, a known substrate of PP1 containing a nuclear localization signal, also prevented nuclear accumulation of NF-κB. Expression of a constitutively active nonphosphorylatable S3A-cofilin in D95N-PP1 cells restored nuclear translocation of NF-κB and IL-10 expression. Subpopulation analysis revealed that defective nuclear translocation of NF-κB was most prominent in CD4+ CD45RA- CXCR3- T cells that included IL-10-producing TH2 cells. Together these findings reveal novel functions for PP1α and its substrate cofilin in T cells namely the regulation of the nuclear translocation of NF-κB and promotion of IL-10 production. These data suggest that stimulation of PP1α could limit the overwhelming immune responses seen in chronic inflammatory diseases.

Keywords: T-cell activation; cytokines; phosphatase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Depolymerizing Factors / metabolism*
  • Anti-Inflammatory Agents / metabolism*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cytokines / metabolism*
  • Humans
  • Immunity / physiology
  • Inflammation / metabolism
  • Interleukin-10 / metabolism*
  • NF-kappa B / metabolism*
  • Protein Phosphatase 1 / metabolism*
  • Protein Transport / physiology
  • Th2 Cells

Substances

  • Actin Depolymerizing Factors
  • Anti-Inflammatory Agents
  • Cytokines
  • IL10 protein, human
  • NF-kappa B
  • Interleukin-10
  • Protein Phosphatase 1